There is no pharmacologic treatment shown to actually reverse dysfunction and restore mitochondrial energetics in vivo in aged muscle. In preliminary experiments we have found that a single treatment with a mitochondrially targeted peptide, SS-31, REVERSES mitochondrial deficits and improves skeletal muscle function in aged mice. Mitochondria sit at the center of cellular aging due to their important role in connecting ATP production, reactive oxygen species production and cell signaling. In skeletal muscle, mitochondria play a critical role in meeting energy demand for muscle function, growth and maintenance. Thus, impaired mitochondrial function with age leads to poor muscle function, exercise intolerance, and poor quality of life of the elderly. There have been many studies testing whether antioxidant treatment delays mitochondrial dysfunction with age and disease. In contrast, we test an innovative strategy to REVERSE mitochondrial deficits and improve muscle function by targeting mitochondrial ATP production independently of reactive oxygen species scavenging. We test the hypothesis that reversing mitochondrial dysfunction with SS-31 treatment will reduce sarcopenia and improve exercise tolerance in aged mice. One of the main limitations to testing interventions to reverse mitochondrial dysfunction is the inability to measure mitochondrial energetics in vivo. We overcome this limitation with new NMR and optical spectroscopy tools developed in our laboratory to study in vivo mitochondrial energetics in mouse skeletal muscle. We propose a unique integrative study that links improvements in mitochondrial function in vivo and ex vivo with improved skeletal muscle function and whole body exercise performance. Aim 1 tests whether SS-31 reverses mitochondrial deficits by increasing mitochondrial ATP production and reducing ROS production independently of ROS scavenging in aged skeletal muscle. Aim 2 tests whether improving mitochondrial function in aged mice reduces sarcopenia, improves skeletal muscle performance, and increases exercise tolerance. This proposal tests a novel strategy for reversal of mitochondrial dysfunction in aged tissues that would represent a new paradigm for developing interventions to improve skeletal muscle function and quality of life in the elderly. PUBLIC HEALTH RELEVANCE: The loss of skeletal muscle function with age (sarcopenia) has significant impacts on society in terms of both loss of quality of life and public health care costs, yet there are no successful pharmacological interventions to reduce sarcopenia. This proposal tests whether SS-31, a novel mt targeted peptide, represents an innovative strategy to reduce sarcopenia and improve exercise tolerance with age by reversing the age-related decline in mitochondrial energetics. Results from this project will have far reaching implications for improving the quality of life in not only the elderly, but also those suffering from mitochondral myopathies.